The invention is in the field of androgenic hormones, more specifically derivatives of 19-nortestosterone.
Testosterone derivatives are known. As a medicine testosterone itself, the natural male hormone, has many known drawbacks as far as methods of administration are concerned. Thus, inter alia, it has a short-lasting activity and is not very potent. The more potent dihydrotestosterone (5xcex1-reduced form of testosterone) is considered a health-risk, notably for the prostate.
A more potent androgen is 7xcex1-methyl-19-nortestosterone (MENT) disclosed in FR 4,521 M and U.S. Pat. No. 5,342,834. An important drawback of MENT, however, is its unfavourable kinetics which limits its use as an orally active androgen.
In the field of pharmaceutical preparations in general it is a common desire for a medicinal agent to be orally active. Oral dosage forms, e.g. solid dosage forms such as tablets and capsules, are among the most widely accepted forms of administration. In the field of androgens, a particular desire exists for the oral administration in connection with a utility such as male contraception. Since in the area of female contraception the word xe2x80x9cpillxe2x80x9d has almost become a synonym for reliable birth-control, it is evident that also in the case of male contraception oral activity is desired, so as to enable providing a male xe2x80x9cpill.xe2x80x9d
Several, mostly very old publications can be mentioned which form the background-art relating to groups of steroid compounds which include 19-nortestosterone derivatives. None of these references teaches orally active androgens.
Thus, in FR 1,432,561, published in 1966, 19-nortestosterones like MENT having an alkyl substituent at C-7 are employed as a starting material for hormonal agents having a double bond between carbon atoms 5 and 6. Alkyl groups other than methyl are not disclosed.
BE 861 224 concerns all possible esters of a wide variety of 17-hydroxysteroids. The disclosure, which dates from 1976, specifically teaches that certain esters are desired for prolonged activity of the steroids. Among the large group of steroids disclosed are oestrogens, anti-oestrogens, androgens and anabolics. A great many possible substituents at various positions is given, among which are methyl and ethyl at C-7.
Chemical Abstracts 110: 95601y (1989) refers to the acetate of 7-allyl-19-nortestosterone as an intermediate in the synthesis of 7-allyloestradiol.
EP 159 739 teaches immunomodulating agents of the oestrane series, including particularly xcex944- and xcex945(10)-oestrene derivatives having an alkyl substituent in position 6 or 7. Said alkyl substituent typically is methyl.
DE 20 43 404 concerns 7xcex2-steroids which have anti-hormonal activities. The alkyl substituent mostly is methyl, but ethyl and propyl are disclosed as well. In the synthesis of 7xcex2-ethyl-19-nortestosterone, which is a compound according to the teaching of DE 20 43 404, the 7xcex1-isomer is formed as well. It is not taught to use this isomer for anything, and the teaching of this document does not distinguish the ethyl or propyl substituents from the methyl moiety.
In a more recent patent application, EP 869 132, 7xcex1-propyl-19-nortestosterone acetate is disclosed as an intermediate in the synthesis of certain estrogenic steroids. The disclosure does not bear any relevance to androgens, nor to any use of the above compound other than as a chemical intermediate.
The background art further includes A. J. Solo et al., in Steroids, 40 (6), 603-614 (1982) which relates to the androgenic and anabolic activities of certain 7xcex1-alkyl testosterones.
It is an object of the invention to provide orally active androgens. A further object of the invention is to provide androgens which in general have a desirable high potency. According to the invention, these and other objectives are achieved by compounds satisfying the general formula I given below. 
wherein
R1 is O, (H,H), (H,OR), NOR, with R being hydrogen, (C1-6)alkyl, or (C1-6)acyl;
R2 is (C2-3)alkyl, isopropyl, (C2-3)1-alkenyl, isopropenyl, 1,2-propadienyl, or (C2-3)1-alkynyl, each optionally substituted by halogen; or R2 is cyclopropyl, or cyclopropenyl, each optionally substituted by (C1-2)alkyl or halogen;
R3 is hydrogen, (C1-2)alkyl, or ethenyl;
R4 is (C1-2)alkyl;
R5 is hydrogen, or (C1-15)acyl;
and the dotted lines indicate optional bonds;
with the proviso that the compound is not (7xcex1,17xcex2)-7-ethyl-17-hydroxyestr-4-en-3-one (7xcex1-ethyl-19-nortestosterone) or a carboxylic ester thereof, and is not (7xcex1,17xcex2)-17-(acetyloxy)-7-propylestr-4-en-3-one (7xcex1-propyl-19-nortestosterone acetate).
The proviso is made in the recognition that the disclaimed compounds have been incidentally disclosed as intermediates in chemical synthesis, in DE 20 43 404 and EP 869 132, respectively. It is stressed that these compounds, as are the other compounds of the invention, are novel for use as a medicine in general, as an androgen, and more particularly as an orally active androgen. Hence, also the compounds disclaimed per se, form part of the present invention and the description hereinafter applies to these compounds as well.
The term (C1-6)alkyl as used in the definition of formula I means a branched or unbranched alkyl group having 1-6 carbon atoms, like methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, and hexyl. Likewise, the term (C1-2)alkyl means an alkyl group having 1-2 carbon atoms and the term (C2-3)alkyl an alkyl group having 2-3 carbon atoms.
The term (C2-3)alkenyl means an alkenyl group having 2-3 carbon atoms. Preferred is ethenyl.
The term (C2-3)alkynyl means an alkynyl group having 2-3 carbon atoms. Preferred is ethynyl.
The term (C1-6)acyl means an acyl group derived from a carboxylic acid having from 1-6 carbon atoms, like formyl, acetyl, propanoyl, butyryl, 2-methylpropanoyl, pentanoyl, pivaloyl, and hexanoyl. Likewise, the term (C1-15)acyl means an acyl group derived from a carboxylic acid having from 1-15 carbon atoms. Also included within the definition of (C1-15)acyl are
[(C3-6)cycloalkyl]carbonyl,
[(C5-6)cycloalkenyl]carbonyl,
benzoyl,
[[(C1-12)alkyl](C3-6)cycloalkyl]carbonyl,
[[(C2-12)alkenyl](C3-6)cycloalkyl]carbonyl],
[[(C2-12)alkynyl](C3-6)cycloalkyl]carbonyl],
[[(C1-10)alkyl](C5-6)cycloalkenyl]carbonyl],
[[(C2-10)alkenyl](C5-6)cycloalkenyl]carbonyl],
[[(C2-10)alkynyl](C5-6)cycloalkenyl]carbonyl],
(C1-9)alkylbenzoyl,
(C2-9)alkenylbenzoyl,
(C2-9)alkynylbenzoyl.
Also included within the definition of (C1-6)acyl or (C1-15)acyl are acyl groups derived from dicarboxylic acids, like hemi-maloyl, hemi-succinoyl, hemi-glutaroyl, and so on. Preferred is hemi-succinoyl.
The term halogen means fluorine, chlorine, bromine, or iodine. When halogen is a substituent at an alkyl group, Cl and F are preferred, F being most preferred.
It is understood that the 7xcex1-substituted nandrolone derivatives of the invention have the natural configurations 5xcex1, 8xcex2, 9xcex1, 10xcex2, 13xcex2, 14xcex1, 17xcex2.
The 7xcex1-substituted nandrolone derivatives of this invention have the natural configurations 5xcex1, 8xcex2, 9xcex1, 10xcex2, 13xcex2, 14xcex1 and 17xcex2, and possess also one or more additional chiral carbon atoms. The compounds may therefore be obtained as a pure diastereomer, or as a mixture of diastereomers. Methods for obtaining the pure diastereomers are well known in the art, e.g. crystallization or chromatography.
Unlike the known compound (MENT), which possesses a 7xcex1-methyl substituent, the compounds of formula I, which can be referred to as 7xcex1-substituted nandrolones, surprisingly have sufficient androgenic potency upon oral administration. None of the above, mostly very old references teaches orally active androgens, let alone that they provide the person skilled in the art with a clue to distinguish any other substituent at C-7 from the widely used methyl moiety.
Preferred compounds have R2 selected from the group consisting of ethyl, ethenyl, ethynyl, propyl, 1-propenyl, 1-propynyl, 1,2-propadienyl, and cyclopropyl.
Even more preferred are compounds in which R1 is oxo, R3 is hydrogen, R4 is methyl or ethyl, and the dotted lines indicate a xcex944 double bond.
Most preferred are those compounds in which R2 is C2, with the highest preference being ethyl or ethenyl.
The invention also pertains to the compounds described hereinbefore as a medicine. The 7xcex1-substituted nandrolones of the present invention being potent androgens, they can be used in, int.al., male contraception and male or female hormone replacement therapy. Thus the invention also pertains to a method of treatment of androgen insufficiency, by administering to a human male or female an effective amount of any of the above compounds. The invention also is in the use of any of the above compounds for the preparation of a medicine for treating androgen insufficiency. In the context of the invention, the term xe2x80x9candrogen insufficiencyxe2x80x9d is to be understood to pertain to all kinds of diseases, disorders, and symptoms in which a male or a female suffers from too low a testosterone level, such as in hypogonadal men. In particular, the androgen insufficiency to be treated by the compound of the invention is the reduction of the testosterone level which a human male incurs as a result of age (the compound of the invention is then used for male hormone replacement therapy), or when he is subject to male contraception. In the context of male contraception, the compound of the invention especially serves to neutralise the effect of regimens of male hormone contraception in which a sterilitant such as a progestagen or LHRH (luteinizing hormone releasing hormone) is administered regularly, e.g. daily, or it is used as the sole male contraceptive substance.
The androgens can be administered principally via any suitable route available to the skilled person. As indicated above, oral administration is preferred, most preferably in the form of a solid dosage unit such as a tablet or a capsule. The invention also relates to pharmaceutical formulations comprising a compound as described hereinbefore and a pharmaceutically acceptable carrier. Thus the carrier may be in a solid form or liquid form, and the formulation may be an oral dosage unit such as a tablet or an oral solution, e.g. in a capsule. Methods and compositions for making such dosage units are well-known to those skilled in the art. For example, conventional techniques for making tablets and pills, containing active ingredients, are described in the standard reference, Gennaro et al, Remington""s Pharmaceutical Sciences, (18th ed., Mack Publishing Company, 1990, see especially Part 8: Pharmaceutical Preparations and Their Manufacture). The compound can also be administered via an implant, a patch, or any other suitable device for the sustained release of an androgen composition.
The dose of and regimen of administration of the compounds of the invention, or a pharmaceutical composition thereof, to be administered will obviously depend on the therapeutic effect to be achieved and will vary with the route of administration, and the age and condition of the individual subject to whom the medicament is to be administered, and/or or the particular contraceptive or HRT regimen in which it is used. Typical dosage amounts are 0.001-5 mg per kg body weight.
The compounds of the invention may be produced by various methods known in the art of organic chemistry in general, and especially in the art of the chemistry of steroids (see, for example: Fried, J. et al, Organic Reactions in Steroid Chemistry, Volumes I and II, Van Nostrand Reinhold Company, New York, 1972).
Essential is the introduction of a saturated or unsaturated 7xcex1-substituent, optionally substituted by halogen, onto the steroid nucleus.
For 7xcex1-substitution, several methodologies are known in the art, among others:
1)xe2x80x94Conjugate addition (1,6-addition) of organocopper reagents to suitably substituted (17xcex2)-17-hydroxyestra-4,6-dien-3-one derivatives, in which the 17-hydroxy group is protected as an ester, e.g. an acetate ester or a benzoate ester, or as an alkoxyalkyl ether, e.g. an ethoxyethyl ether or a tetrahydropyranyl ether, or as a silyl ether, e.g. a trimethylsilyl ether or a t-butyldimethylsilyl ether [for conjugate additions of organocopper reagents, see Lipshutz, B. H. et al in Org. Reactions 41, p. 135, Wiley, New York, 1992].
2)xe2x80x94Transition metal-mediated (TiCl4, AlCl3, ZrCl4, etc.) reaction of an organosilicon compound with a (17xcex2)-17-hydroxyestra-4,6-dien-3-one derivative as described above [again formal 1,6-addition; see e.g. Nickisch, K. et al, Tetrahedron Lett. 29, 1533 (1988)].
3)xe2x80x94Base-catalyzed conjugate addition (1,6-addition) of a dialkyl malonate or alkyl cyanoacetate to a (17xcex2)-17-hydroxyestra-4,6-dien-3-one derivative as described above [see e.g. Cruz, R. et al, Austr. J. Chem. 35, 451 (1982)].
4)xe2x80x94Lewis acid-catalyzed reaction of an estra-1,3,5(10),7-tetraene derivative with an aldehyde (Prins reaction), resulting in an estra-1,3,5(10),8-tetraene-7-alkanol derivative [see: Kuenzer, H. et al, Tetrahedron Lett. 32, 743 (1991)].
5)xe2x80x94Alkylation at C-7 of an estra-1,3,5(10)-trien-6-one derivative [see: e.g. Tedesco, R. et al, Tetrahedron Lett. 38, 7997 (1997)].
6)xe2x80x94Conjugate addition (1,4-addition) of a suitable nucleophilic reagent (e.g. an organocopper reagent) to a 6-[alkyl(or aryl)sulfonyl]estra-1,3,5(10),6-tetraen derivative [Schering AG, DE 42 18 743 A 1].
Using these methodologies, the compounds of the invention can further be prepared using standard methods known in the art.